Aminomethyldibenzobicycloalkenes



United States Patent 3,441,567 AMINOMETHYLDIBENZOBICYCLOALKENES EugeneE. Galantay, Morristown, N.J., assignor to Sandoz Inc., Hanover, NJ. NoDrawing. Filed June 1, 1965, Ser. No. 460,521 Int. Cl. C07d 93/10,87/26; C07c 87/38 US. Cl. 260-293 10 Claims ABSTRACT OF THE DISCLOSUREThe compounds are Z-aminomethyl-1,2,6,7-tetrahydro-(1lbH)-benzo[j]benz[c,d]azulenes and 2-aminomethyl- 1,2,6,7,8,l2bhexahydrocyclopenta[d,e]dibenzo[a,d]cyclooctenes, e.g.,2-methylaminomethyl-l,2,6,7-tetrahydro- (1lbH)-benzo[j]benz[c,d]azulene.The compounds are useful pharmaceutically.

This invention is directed to two series of pharmaceutically acceptableCNS (central nervous system) active aminomethyldibenzobycycloalkenes ofthe formula wherein X is either dimethylene (-CH CH i.e. for one series,or trimethylene (CH CH CH i.e. for the other series;

Y is either I e.g. primary amino (HN secondary amino (,8-

phenethylamino and isopropylamino) and tertiary amino(N-methyl-N-propylamino); lower alkyleneimino, e.g. ethyleneimino,propyleneimino, pyrrolidyl, piperidyl, hexahydroazepin-l-yl andoctahydroazocinl-yl; or saturated heteromonocyclic-imino, e.g. loweralkylpiperazinyl (ethylpiperazinyl), morpholino, thiomorpholino andpyrazolidino; and

each of R and R is, independently, either a hydrogen atom; lower alkyl,e.g. methyl, ethyl, propyl, isopropyl and butyl; or ar(lower)alkyl, e.g.benzyl;

to pharmaceutically acceptable acid addition salts thereof and to theintermediates in the preparation thereof. When X is dimethylene,compounds I are Z-aminomethyll,2,6,7tetrahydro-(l-1bI-I)-benzo[j]benz[c,d] azulenes; When X is dimethylene,compounds I are Z-aminomethyl 1,2,6,7,8,12bhexahydrocyclopenta[d,e]dibenzo[a,d] cyclooctenes. The amino in bothcases is defined by Y.

Compounds I have two asymmetric carbon atoms and, thus, fourstereoisomeric forms. The intermediates with asymmetric carbon atomsalso exist as chemical individuals. All of the stereoisomers are Withinthe scope of the invention, even though some of the stereoisomeric pairsare preferably formed in the reactions described in the examples. Asdesired, single stereoisomers of compounds I or those of theintermediates are isolated by methods known to the art-skilled. Thus,the so-called geometric (cisand trans-forms) or diastreoisomers areseparated from each other by, e.g., fractional crystallization, where-"ice as single racemates are split into optical enantiomers by theprocess known as resolution. It is understood that stereoisomeric formsof the same compound I may have quantitatively or qualitativelyditferent physiological action.

Compounds I and pharmaceutically acceptable acid addition salts thereofare useful as tranquilizers. They are administered either orally orparenterally instandard dosage forms, e.g. tablets, capsules. Theaverage daily dosage varies within the range from 20 to milligrams.

Each of the pharmaceutically active compounds of this invention may be,e.g., incorporated, for oral administration, in a tablet as the soleactive ingredient. A typical tablet is constituted by from 1 to 3percent binder, e.g. tragacanth; from 3 to 10 percent disintegratingagent, e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum;from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an averagedosage of active ingredient; and q.s. 100 percent of filler, e.g.lactose; all percentages being by weight. Tablets are prepared accordingto standard tabletting techniques, which are well-known in the art,employing the necessary amounts of conventional granulating liquids,e.g. alcohol SD-30 and purified water. An exemplary tablettingformulation for the instant active com- Alcohol SD-30, purified water,q.s.

Among the pharmaceutically acceptable acid addition salts are salts oforganic acids, e.g. tartaric acid; inorganic acids, e.g. hydrochloricacid, hydrobromic acid and sulfuric acid; monobasic acids, e.g. analkylsulfonic acid, such as methylsulfonic acid (HgC-SOgH) dibasicacids, e.g.

tartaric acid and succinic acid; tribasic acids, e.g. phosphoric acidand citric acid; saturated acids, e.g. acetic acid; ethylenicallyunsaturated acids; e.g. maleic acid and fumaric acid; and aromaticacids, e.g. salicyclic acid and arylsulfonic acids, such as phenylsulfonic acid. The only limitation on the acid selected is that theresulting acid addition salt be pharmaceutically acceptable; the aciddoes not nullify the therapeutic properties of compounds I. It ispreferred, however, to select an acid so that the salt therewith iswater-soluble; tartaric acid and succinic acid are preferred for thispurpose.

The pharmaceutically acceptable acid addition salts are preparedaccording to standard methods well known to the art-skilled.

In the preparation of compounds I and the intermediates therefor, thereactions are independent of Whether X is dimethylene or trimethylene.Examples wherein X is dimethylene are thus equally illustrative of thepreparation of the corresponding compounds wherein X is trimethylene.Reaction schemes for preparing compounds I follow on the next page.

Both compound 11 wherein X is dimethylene and compound II wherein X isthimethylene are known compounds.

Reaction A is a condensation of II with tertiary-butyl acetate in thepresence of diethylamino magnesium bromide, following the general methodof K. Sisido, H. Nozaki and O. Kurihara, JACS, 74, 6254 (1952), indiethylether, tetrahydrofuran or dioxane as solvent.

Reaction B is the Reformatsky Reaction with H C (Hal) -CO-O-R' wherein Ris lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl; and Halis preferably a bromine atom (Br), but may be either a chlorine atom(-Cl) or an iodine atom (I);

followed by saponification and dehydration.

Reaction B is alternatively eflected with a (lower alkoxy) acetylene[c.g. methoxyacetylene, propoxyacetylene and butoxyacetylene, butpreferably ethoxyacetylene], followed by rearrangement andsaponification of 10 the initial product @l) II III X Reaction C takesplace in an inert solvent, such as benzene, toluene and xylene, at theboiling point of the w 1s v:

CEO-O-(lower alkyl) HC-C O-O-(lower alkyl) (IIIa) (IVa) according to thegeneral method described by G. F. Arens, Advances in Organic Chemistry,vol. II, pages 157 to 161, Interscience Publishers, Inc., New York, NewYork, 1960.

65 for this purpose. At least one half mole of P 0 for each mole of (1V)and 1.0 mole of P 0 for each mole of (III) are advantageously employed.Reactions D and E are carried out at from to 150 C. preferably in therange of from to C.

When other cyclization reagents are employed in reactions D and E, sideproducts may be formed to a greater extent and/or the desired productmay undergo further reactions, e.g. dimerization and condensation.

Reactions F and G are either chemical reductions or 75 standardhydrogenations (preferred) at pressures from 1 to 500 atmospheres andtemperatures from to 150 C. in a solvent, such as dioxane, ethanol andethyl acetate, preferably With palladium catalyst.

Reaction H (cyclization) is carried out preferably with polyphosphoricacid at a temperature from 40 to 200 C., but other methods, e.g.cyclization in liquid anhydrous hydrofluoric acid of Friedel-Craftscyclization of the corresponding chloride, may also be used.

Reaction I is a reduction according to standard procedures. Whilereduction with lithium aluminum hydride is preferred, other complexhydrides, such as sodium and lithium borohydride, or other redutcionmethods, such as the MeerWein-Ponndorf reduction or catalytichydrogenation, may alternatively be employed.

Reaction J is either a chemical redutcion with a complex hydride, suchas lithium aluminum hydride and sodium borohydride, or it is a catalytichydrogenation.

Reaction K is with hydrogen bromide in benzene at a temperature from 4to 30 C.

Reaction L is with a salt of hydrogen cyanide, preferably with sodiumcyanide in dimethylformamide (DMF).

Reaction M is a reduction, preferably with lithium aluminumhydridealumiuum chloride complex.

Reaction N is an alkylation (Leuckart Reaction).

Reaction 0 is Wtih 1,5-dibromopentane in toluene under reflux.

Reaction P is the Reformatsky Reaction.

Reaction Q is dehydration followed by hydrogenation.

Reaction R is hydrazinolysis.

Reaction S is with alkylnitrile, e.g. butylnitrile, in admixture Withhydrogen chloride in glacial acetic acid/diethylether, or it is withsodium azide in glacial acetic acid.

Reaction T is the Curtius Rearrangement.

Reaction U is with absolute ethanol under reflux.

Reaction V is reduction with a complex hydride, e.g. lithium aluminumhydride.

Reaction W is an acid hydrolysis.

Reaction X is a hydrolysis with a strong base.

Reaction Y is an alkylation (Leuckart Reaction).

In the examples the parts and percentages are by weight unless otherwisespecified, and the temperatures are in degrees Centigrade. Therelationship between parts by Weight and parts by volume is the same asthat between the kilogram and the liter.

EXAMPLE 1 6,7-dihydro-2H-benzo[j]benz[c,d] azulen-Z-one To a stirredsolution of 40 parts commercial polyphosphoric acid in 400 parts byvolume of glacial acetic acid, add in small portions 40 parts of5-hydroxy-5-(carbotert.-butoxymethy)10,1l-dihydro-SH-dibenzo[a,d]cycloheptane 1 and maintain the resultingred solution at 100 for 15 hours. Pour the reaction mixture onto ice,and dissolve the resulting orange precipitate in chloroform. Wash theobtained chloroform solution with 2N sodium hydroxide solution toseparate S-carboxymethylidene-IO,ll-dihydro-SH-dibenzo[a,d]cycloheptene; then evaporate the remainingchloroform solution to give 17.5 parts of the crude6,7-dihydro-2H-benzo[j1benz[c,d]azulen-2-one. Purify by chromatographyon silica gel to separate the compound of this example from5-methylidene-10,11-dihydro-5H dibenzo[a,d]cycloheptene [1.8 parts,melting point (M.P.) 5658]. The pure product is an orange solid, M.P.6667; oxime, M.P. 134; dinitrophenylhydrazone, M.P. 258.

3'. Org, Chem. 27, 230 (1962).

6 EXAMPLE 2 6,7-dihydro-2H-benzo [j]benz[c,d] azulen-2-one CH CH Admix40 parts ofS-carboxymethylidene-lO,1l-dihydro-5H-dibenzo[a,d]cycloheptene (seeExample 1) with 60 parts of polyphosphoric acid in 600 parts of glacialacetic acid and reflux the resulting soltuion at for 18 hours. Pour thereaction mixture onto ice, and dissolve the resulting orange precipitatein chloroform. Wash the obtained chloroform solution with 2N sodiumhydroxide solution to separate any unreacted 5-carboxymethylidene-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene; then evaporate the remainingchloroform solution to give 31 parts of the crude 6,7-dihydro-2H-benzo[j] benz [c,d] aZulen-2-one. Purify by chromatography on silica gel toseparate the compound of this example from 5-methylidene-10,11-dihydroSH-dibenzo[a,d]cycloheptene, M.P. 56 -58. The pure product is an orangesolid, M.P. 66 67.

EXAMPLE 3 2,6,7,9-tetrahydrocyclopenta [d,e] dibenzo [a,d]cycloocten-2-one CH -CH CH React 50 parts of5,10,11,12-tetrahydrodibenzo[a,d] cycloocten-S-one with the Grignardderivative of 15.75 parts of ethoxy-acetylene in tetrahydrofuran,following the general method described by Arens, G. F., vol. II, pp. 157to 161, Advances in Organic Chemistry, Interscience Publishers, Inc.,New York, New York, 1960. Treat the crude product with acid, thensaponify with alcoholic potassium hydroxide to isolate, afteracidification, 5- carboxymethylidene 5,10,1l,12-tetrahydrodibenzo[a,d]cycloocetcne, M.P. 172. Dissolve 40 parts of the foregoing product with60 parts of polyphosphoric acid in 600 parts of glacial acetic acid, andheat the resulting solution under reflux for 30 minutes. Pour thereaction mixture onto ice, and dissolve the resulting orange precipitatein chloroform. Wash the obtained chloroform solution with 2N sodiumhydroxide solution, with water and dry; then evaporate the remainingchloroform solution to obtain 53.2 parts of an orange oil, whichconsists of 85% of the desired 2,6,7,S-tetrahydrocyclopenta[d,e]dibenzo[a,d]cycloocten-Z-one and 15% of side product, 5 methylidene5,10,11,12 tetrahydrodibenzo[a,d] cyclooctene. Separate the pure titlecompound by chromatography.

EXAMPLE 4 l,2,6,7-tetrahydro-(11bH)-benzo[j]benz[c,d] azulen-Z-one Ch-CH EXAMPLE S-carboxymethyl-S, 10,1 1, IZ-tetrahydrodibenzo a,d]cyclooctene H -COOH Stir a mixture of 4.15 parts ofS-carboxymethylidene- 5,l0,l1,12-tetrahydrodibenzo[a,d]cyclooctene (seeExample 3), 0.2 part of palladium-charcoal catalyst and parts by volumeof dioxane in a hydrogen atmosphere until the theoretical amount ofhydrogen is absorbed. Filter the catalyst from the product, andevaporate the filtrate to obtain the title compound, M.P. 205206, inquantitative yield.

EXAMPLE 6 5-carboxymethyl-10,1 l-dihydro-SH-dibenzo [a,d] cycloheptene1,2,6,7-tetrahydro-(l1bH)-benzo[j]benz[c,d]azulen-2-one m crr To 1600parts of commercial polyphosphoric acid (P 0 content of 82% to 84%)vigorously stirred at 92 add, in one portion, 16 parts of5-carboxymethyl-10,11 dihydro-5H-dibenzo[a,d]cycloheptene and maintainstirring between 90 and 93 for three hours. Pour produced mixture onto4000 parts of ice, filter and wash separated solids with 2 N sodiumcarbonate solution to remove unchanged starting material. Rewash saidsolids with Water, ethanol and diethylether. Recrystallize the thus-Washed solids from 800 parts of boiling dimethylformamide to obtainabout 90 parts of the pure title compound, M.P. 218. Recover unchangedstarting material from soda and aqueous washings by acidification.

(Ill -CH H- OR (a) Reflux for 3 hours a mixture consisting of 6.75 partsof 1,2,6,7 tetrahydro-(11bH)-benzo[j]benz[c,d] azulen-2-one, 1 part oflithium aluminum hydride and 200 parts of dry diethylether. Decomposethe excess lithium aluminum hydride -with dilute sulfuric acid undercooling. Distill 01f the ether and obtain the title compound, M.P.161-163, by filtration and recrystallization from eitherethanol/diethylether or benzene.

(b) Admix 0.3 part of sodium borohydride with a solution of 1 part of6,7-dihydro-(2H)-benzo [j]'benz[c,d] azulen-2-one in 20 parts of ethanol(previously cooled to '70), and warm the obtained mixture to roomtemperature over a period of three hours. After two more hours at roomtemperature, decompose excess borohydride with aqueous acetic acid andextract resultant with chloroform to obtain (after recrystallization ofthe chloroform extract from benzene) 0.9 part of title compound, M.P.159.

- EXAMPLE 9 2-bromo-1,2,6,7-rtetrahydro-(1 1bH)-benzo [j benz [c,d]azulene CH CH CH CH Add, to a refluxing mixture of 50.0 parts of1,2,6,7- tetrahydro (llbH) benzo[j]benz[c,d] azulen 2 one, 31.3 parts ofactivated zinc and 1500 parts per volume of benzene-toulene (1:1), overa period of 30 minutes, a solution of 80.0 parts of ethyl bromoacetatein 50 parts per volume of benzene. Continue refluxing for an additional2.5 hours. Cool, decompose the complex with 500 parts per volume ofsaturated ammonium chloride solution. Work up the organic phase toobtain 76 parts of an oil; isolate 50.0 parts of the crude product (M.P.98104) by trituration with diisopropyl ether. The pure product,

after recrystallization from alcohol, has a M.P. of 104 to 105.

EXAMPLE 11 Z-ethOxycarbonyl-1l,2,6,7-tetrahydro-(11bH) benzo[j] benz[c,d] azulene (Ili -CH i T I Reflux a mixture of 35 parts of21ethoxycarbonyl-2- hydroxy 1,2,6,7 tetrahydro (11-bH) benzo[j]benz[c,d]azulene, 1.3 parts of p-toluenesulfonic acid in 300 parts by volumeof toluene under an azeotropic Water separation trap until about (45minutes) about 2 parts by volume of water are collected in the trap.Cool, wash the toluene solution with sodium hydrocarbonate solution andwater, dry and evaporate to obtain 33.7 parts of an oil.

Hydrogenate the solution of the latter oil in 150 parts by volume ofethyl acetate in the presence of 1.0 part of palladium-carbon (10%)catalyst, under 50 p.s.i.g. of hydrogen pressure. After uptake of thecalculated amount of hydrogen, filter the solution and evaporate same toobtain 33.7 parts of the product, M.P. 75 to 79. [The pure productmelts, after recrystallization from ethanol, at 78 to 80.]

EXAMPLE 12 Z-hydrazinocarbonyl-1-1,2,6,7-tetrahydro-( 1 1bH)-benzo[J'lbeuz[c,d] azulene CH -Ch CH CH -CONZE H EXAMPLE l32-azidocarbonyl-1,2,6,7-tetrahydro-(l1bH)=benzo[j]benz [c,d] azulene Gil-CH Dissolve 16.5 parts of Z-hydrazinocarbonyl-1,2,6,7- tetrahydro- 1lbH) -beuzo [j benz [c,d] azulene by heating in 125 parts by volume ofglacial acetic acid. Cool, add thereto 125 parts by volume of ether andintroduce hydrogen chloride gas. To the stirred suspension, at 5 andover a period of 45 minutes, add 34 parts by volume of butyl nitrite.Reduce the volume of the mixture to about its third by evaporation invacuo, at temperatures not exceeding 20. Filter oir the product, washthoroughly with cold water and dry at room temperature, yielding 15.3parts of title compound, M.P. 9193.

10 EXAMPLE 14 1,2,6,7-tetrahydro-(11=bH)-benzo[j]benz[c,d]azulenyl-2-methylisocyanate Reflux a suspension of 15.3 parts of2-azidocarbonyll,2,6,7 tetrahydro (ll-bH) benzo [j]benz[c,d] azulene in300 parts by volume of toluene for 60 minutes. Filter from a smallamount of still undissolved solid and evaporate to obtain 15.2 parts ofthe oily product.

EXAMPLE 15 2-carbethoxyaminomethyl-1,2,6,7-tetrahydro-( 1 lbH- benzo [j]benz[c,d] azulene CH CH 2 CH-CH -NHCOOC H Reflux 15.2 parts of1,2,6,7-tetrahydro-(11'bH)-benzo [j]benz[c,d]azulenyl-Z-methylisocyanatewith 350 parts by volume of absolute ethanol for 15 minutes. Evaporatethe resultant to obtain 15.9 parts of a solid, M.P. The pure product,after chromatography and recrystallization from ether-petroleum ether,has a M.P. of 108-110.

EXAMPLE l6 2-methylaminomethyl-1,2,6,7-tetrahydro-(11bH)- benzo [j] benz[c,d] azulene EXAMPLE 17 Z-cyauo-1,2,6,7-tetrahydro-(11bH)-benzo[j]benz[c,d] azulene CH CH c --i in H-CN Add at room temperature, to amixture of 23.6 parts of sodium cyanide and parts by volume ofdimethylformamide (previously heated to reflux and thereafter recooled)32.8 parts of Z-bromo-l,2,6,7-tetrahydro-(11bH)- benzo[j]benz[c,d]azulene, and stir mixture for 19 hours. Add 1000 parts byvolume of water and extract the crude product (27.8 parts) withchloroform.

EXAMPLE 18 Z-aminomethyl-1,2,6,7-tetrahydro-( 1 lbH) benzo [j] benz[c,d] azulene Admix 1.79 parts of lithium hydride and 6.28 parts ofaluminum chloride under 700 parts by volume of dry ether. Add to therefluxing mixture, by the Soxhlet method, 10.50 parts of crude2-cyano-1,2,6,7-tetrahydr0- (1lbH)-benzo[j]benz[c,d]azulene and, aftercompleting this addition, continue refluxing for 3 hours. Decompose thecomplex with 250 parts by volume of 25% potassiumsodium tartratesolution, decant ether phase. Add to the aqueous phase 100 parts byvolume of 50% sodium hydroxide solution and maintain mixture at 80 for12 hours. Cool the mixture and extract with ether. Into the unified anddried ethereal solution, introduce hydrogen chloride gas to obtain 9.33parts of the cyanochloride of the product, M.P. after recrystallizationfrom alcohol 263 to 268.

EXAMPLE 19 Z-dimethylaminomethyl-1,2,6,7-tetrahydro- 1 1bH)- benzo [j]benz[c,d] azulene Heat a mixture of 8.9 parts of 2-aminomethyl-1,2,6,7-tetrahydro- 1 lbH) -benzo [j] benz [c,d] azulene (free base), 10.1 partsof 80% formic acid and 7.9 parts of 40% formaldehyde solution to 100until the evolution of carbon dioxide ceases. Add thereto 2 parts ofconcentrated hydrochloric acid and evaporate mixture in vacuo. Theresidue constitutes the crude produce in its hydrochloric acid saltform. Purification is achieved by liberating the free base with aqueousammonia, extraction with ether and introduction of hydrogen chloride gasinto the washed and dried ethereal solution, whereupon the hydrochlorideof the product precipitates.

Reacting 2 methylaminomethyl 1,2,6,7 tetrahydro(1lbH)-benzo[j]benz[c,d]azulene (free base) under the above conditionsyields the same product.

EXAMPLE 20 2-N-piperidylmethyl-l,2,6,7-tetrahydro- (l 1bH)- benzo [j]benz [c,d] azulene CH -CH Admix 2.51 parts of the title compound ofExample 18, 2.30 parts of 1,5-dibromopentane and 20 parts by volume oftoluene and reflux the resultant for 3 hours. Add thereto 1.7 parts ofsodium hydrocarbonate and 10 parts by volume of toluene and continuerefluxing for an additional 15 hours. Cool the resultant to roomtemperature; add ch10- roform thereto; and wash the toluene/chloroformsolution with water. Dry the above solution and precipitate thehydrochloride of the product by addition thereto of ethereal hydrogenchloride.

Examples 17 to 20 illustrate a reaction scheme alternative to thatillustrated by Examples 10 to 16. The latter is longer, butstereospecific. The shorter process yields the diastereoisomers whichare separated into chemical individuals by known methods.

The invention will be understood from the foregoing description. Variouschanges may be made in the processes, the intermediates and the finalproducts without departing from the spirit or scope of the invention orsacrificing its material advantages. The processes, the novelintermediates and the final products hereinbefore described are merelyillustrative embodiments of the invention.

What is claimed is:

1. A pharmaceutically acceptable compound which, in free base form, isof the formula H C R H 0 -n\R 3. 2methylaminomethyl-1,2,6,7-tetrahydro-(11bH)- benzo[j]benz[c,d] azulene.

4. 2 dimethylaminomethyl 1,2,6,7 tetrahydro-(11bH)-benzo[j]benzo[c,d]azulene.

5. A pharmaceutically acceptable compound which, in free base form, isof the formula Cli -CH c n I 3 c (3H CH2 wherein n is an integer from 1to 6, inclusive.

6. 2 N piperidylmethyl-l,2,6,7-tetrahydro-(1lbH)- benzo [j] benz[c,d]azulene.

7. A pharmaceutically acceptable compound which, in free base form, isof the formula wherein W is a member selected from the group consistingof alkylpiperazinyl having from 1 to 4 carbon atoms in the alkylportion, morpholino, thiomorpholino and pyrazolidino.

8. A pharmaceutically acceptable compound which, in free base form is ofthe formula wherein each of -R and R is a member selected from the groupconsisting of a hydrogen atom, alkyl having from 1 to 4 carbon atoms,benzyl and phenethyl.

9. A pharmaceutically acceptable compound which, in free base form, isof the formula CH2-CH2-CH 5 c n I I H2C-- (IJH CH2 H c N wherein n is aninteger from 1 to 6, inclusive. 10. A pharmaceutically acceptablecompound which,

in free base form, is of the formula CHZ-CHZ-CH H 2 c i and pyrazolidmo.

References Cited UNITED STATES PATENTS 3,358,027 12/1967 Stclt 260-32681HENRY R. IILES, Primary Examiner.

H. I. MOATY, Assistant Examiner.

US. Cl. X.R.

